Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis
Authors: Fajri Gafar, Roeland E. Wasmann, Helen M. McIlleron, Rob E. Aarnoutse, H. Simon Schaaf, Ben J. Marais, Dipti Agarwal, Sampson Antwi, Nguyen D. Bang, Adrie Bekker, David J. Bell, Chishala Chabala, Louise Choo, Geraint R. Davies, Jeremy N. Day, Rajeshwar Dayal, Paolo Denti, Peter R. Donald, Ephrem Engidawork, Anthony J. Garcia-Prats, Diana Gibb, Stephen M. Graham, Anneke C. Hesseling, Scott K. Heysell, Misgana I. Idris, Sushil K. Kabra, Aarti Kinikar, Agibothu K. Hemanth Kumar, Awewura Kwara, Rakesh Lodha, Cecile Magis-Escurra, Nilza Martinez, Binu S. Mathew, Vidya Mave, Estomih Mduma, Rachel Mlotha-Mitole, Stellah G. Mpagama, Aparna Mukherjee, Heda M. Nataprawira, Charles A. Peloquin, Thomas Pouplin, Geetha Ramachandran, Jaya Ranjalkar, Vandana Roy, Rovina Ruslami, Ira Shah, Yatish Singh, Marieke G.G. Sturkenboom, Elin M. Svensson, Soumya Swaminathan, Urmila Thatte, Stephanie Thee, Tania A. Thomas, Tjokosela Tikiso, Daan J. Touw, Anna Turkova, Thirumurthy Velpandian, Lilly M. Verhagen, Jana L. Winckler, Hongmei Yang, Vycke Yunivita, Katja Taxis, Jasper Stevens, Jan-Willem C. Alffenaar
Journal: European Respiratory Journal (2022)

Background Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. Methods We systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC 0–24 ) and peak plasma concentration ( C max ) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC 0–24 and C max were assessed with linear mixed-effects models. Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC 0–24 were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L −1 ), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L −1 ), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L −1 ) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L −1 ). Our multivariate models indicated that younger age (especially &lt;2 years) and HIV-positive status were associated with lower AUC 0–24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC 0–24 for isoniazid and pyrazinamide. N -acetyltransferase 2 rapid acetylators had lower isoniazid AUC 0–24 and slow acetylators had higher isoniazid AUC 0–24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC 0–24 . Conclusions This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.